Glucose-responsive nanozyme hydrogel for glycemic control and catalytic anti-infective therapy in diabetic wound healing

Diabetes-induced impairment in glycemic regulation delays wound healing by promoting bacterial infection, oxidative stress, and vascular injury. To address these challenges, we developed a glucose-activated, self-switchable nanozyme-hydrogel platform capable of intelligent, on-demand insulin release synchronized with blood glucose fluctuations, thereby achieving closed-loop glycemic control while promoting tissue repair. This multifunctional system integrates glucose oxidase (GOx) and insulin within bimetallic Zn-Fe metal organic framework nanoparticles (MOF(Zn-Fe)/GOx/INS), which are embedded in a ROS-responsive hydrogel. Under hyperglycemic conditions, GOx catalyzes glucose oxidation to gluconic acid and H₂O₂, generating a mildly acidic microenvironment. This acidity triggers the peroxidase-like activity of MOF(Zn-Fe) to produce hydroxyl radicals (•OH), enabling potent antibacterial effects and accelerating MOF degradation, thereby releasing insulin to restore normoglycemia. As glucose levels normalize, catalytic activity is self-terminated to prevent hypoglycemia. In vitro and in vivo studies confirmed robust antibacterial performance, enhanced angiogenesis, anti-inflammatory activity, and accelerated wound closure. Transcriptomic profiling further revealed upregulation of regenerative pathways and suppression of inflammatory and apoptotic signaling. This glucose-activated autonomous system provides a powerful strategy for diabetic wound management through synergistic glycemic control, anti-infection efficacy, and tissue regeneration.